Expert Discusses CRC Developments, Importance of Molecular Profiling

Caroline Seymour

Published: Sunday, Feb 03, 2019

Pashtoon M. Kasi, MD, MBBS, MS

Liquid biopsies may not be ready for prime time use in colorectal cancer (CRC), but they stand to show the importance of identifying clinically relevant mutations that can direct future treatment decisions, said Pashtoon M. Kasi, MD, MBBS, MS.

“There are many subsets of CRC, including RAS, RAF, HER2, NTRK, microsatellite instability-high (MSI-H), and high tumor mutational burden. Previously, some of these mutations were only prognostic. Now, we have options for patients with BRAF V600E mutations,” said Kasi. “Additionally, we have anti-HER2 drugs or trials, as well as drugs [targeted against] NTRK fusions. As you can see, it is a very heterogenous disease in which sidedness also plays a role, but we're moving towards individualizing therapy for patients.”

In an interview with OncLive, Kasi, an assistant professor of oncology and senior associate consultant in the Division of Hematology/Oncology at Mayo Clinic, provided an overview of the potential for liquid biopsies in CRC and advances being made in the treatment landscape.

OncLive: Where do liquid biopsies stand in CRC?

Kasi: Liquid biopsies are done through circulating tumor DNA testing; it’s something that has rapidly made its way into research and is now making its way into practice. The most recent guidelines that came from the 2018 ASCO [Board of Directors] meeting in March 2018 are showing promise; however, they’re not ready for prime time. The only FDA-approved indication for liquid biopsies is in the sphere of lung cancer.

If you look at all the papers and abstracts that came from the 2018 ASCO Annual Meeting, and now, the 2019 ASCO Gastrointestinal Cancers Symposium, there is a great enthusiasm for the approach because of its sensitivity and specificity—at least in the metastatic setting. For early-stage cancers, it's still early in research. In the metastatic setting, these biopsies are able to pick up HER2, or clinically relevant mutations, such as BRAF or RAS.

This approach is helpful in patients where you may not have the tissue biopsy available. If the tissue biopsy is not sufficient, the liquid biopsy can help complement it. It's not meant to replace the solid tumor tissue testing, but it is an adjunct to tissue biopsy.

Liquid biopsies help us identify acquired mechanisms of resistance, including RAS, and RAF wild-type tumors that acquire RAS mutations or EGFR mutations. Those are things you can pick up on a liquid biopsy that you wouldn't be able to pick up on [standard] tissue testing. It’s not feasible to do [tissue] biopsies again and again. HER2 is also an acquired mechanism of resistance that can be picked up by a liquid biopsy; it’s found in approximately 4% of patients in the acquired setting. We recently had the agnostic approval of NTRK inhibitors for NTRK fusion–positive patients, which constitute about 1% to 2% of CRCs as well.

Could you elaborate on ongoing research efforts in this area?

One of the most exciting things, in terms of the use of this approach in the metastatic setting, is in a clinical trial setting. One of the clinical trials that is being developed as we speak is going to be a master protocol, where each treatment arm may be determined by the patient’s liquid biopsy results. The study is being led by many academic institutions.

As of right now, different arms are being developed based on the aberration found in each patient. We already have the HER2 arm open, in which there will be matched therapy based on circulating tumor DNA testing. Ongoing research is testing its use earlier on to determine which patients will benefit from chemotherapy and who may not need it.

Could you discuss the BEACON trial?

The BEACON trial is one of the most exciting trials that we had updates for at the 2019 ASCO Gastrointestinal Cancers Symposium. The trial is focused on patients with BRAF V600E-mutated CRC led by Scott Kopetz, MD, PhD, FACP, of The University of Texas MD Anderson Cancer Center, and Axel Grothey, MD, of West Cancer Center. These patients comprise an unmet need; their survival in the second-line setting is about 4 to 6 months; [outcomes in these patients are] up to 3 times worse than those of patients who don’t have the BRAF V600E mutation. These patients really don't have too many options. Historically, BRAF inhibitors didn't work. The combination of BRAF inhibitors with MEK inhibitors did not show much promise.